Many people suffer from urinary incontinence. Often, it is believed that incontinence is mainly due to a reduced function of the bladder sphincter (i.e. the muscle keeping the bladder closed) and adjunct parts of the urogenital tract. However, this view is obviously not correct. While under certain circumstances a reduced sphincter function can be found which often is related with a location of the bladder too deep inside the pelvic cavity, this is only one aspect and one possible cause of incontinence. The bladder function can be seen as a delicate balance between the activity of the sphincter and the detrusor, i.e. the muscle which is responsible for getting the urine out of the bladder during voiding and which is represented by the muscular wall of the bladder. Not the malfunction or reduced tension of the sphincter is often the main cause, but rather the imbalance between the tonus of the sphincter and the function of the detrusor.
The bladder detrusor and sphincter combination is one of the two smooth muscle groups which human beings (and also some animals) learn to control directly via central functions while all other smooth muscles are not voluntarily controlled (the other smooth muscle represents the sphincter of the anus). As can be easily understood, this control of the balance involves peripheral and central neuronal functions, to enable the voluntary micturation response. But it also contains in-voluntary components as filling of the bladder finally triggers the urgent need for micturation.
This complex circuit and delicate balance, involving filling of the bladder due to renal function, sphincter activity to keep the bladder close and detrusor activity induced by filling but triggered also by CNS driven nerve function, can easily be disturbed. For example, stress often can result in a need for micturation without an adequate filling of the bladder. Also, the absence of ability to reach a toilet in many persons triggers such an urgency and excessive exaltation such as during laughter can result in in-voluntary voiding.
While these examples indicate how delicate the balance is, this is not a disease. But such disturbances can results in disease stages if the disturbance persists over a long period. The cause for such a disturbance can be manifold. A chronic stress syndrome can result in urgency and incontinence, but also other diseases can cause urgency and ultimately incontinence. Such diseases can be but are not limited to prostate hyperplasia, infections of the urinary tract, different CNS diseases such as Parkinson's disease, Alzheimer's disease, dystonia, anxiety disorders, post traumatic stress syndrome and others. Urge incontinence or inadequate urgency is also a frequent side effect of neuroleptic treatment.
It is to be noted that the disease is not the incontinence which only is a possible symptom but rather the un-physiological urgency, i.e. the need to go to the toilet despite the fact that that would not be necessary on the basis of filling of the bladder. Such diseases may be related to morphological changes in the urinary tract such as hyperplasia or hypertrophy of the bladder wall, inflammation or hypertrophy of the mucosa, miss-placement of the bladder or morphological changes in other parts of the urogenital tract such as prostate or urethra, but in many cases no morphological changes can be found as functional changes including functional changes in the central control of micturation may be the underlying cause. This is especially the case in children suffering from overactive bladder and ultimateively from incontinence (mostly nocturnal incontinence) which can be a big problem for both, children and families.
According to a comprehensive review of terminology of lower urinary tract function/dysfunction, the International Continence Society (ICS) has recommended the use of the terms overactive bladder syndrome (OAB) and detrusor overactivity for this group of diseases. Detrusor overactivity is defined as a urodynamic observation characterized by involuntary detrusor contractions during the filling phase that may be spontaneous or provoked. Detrusor overactivity is subdivided into idiopathic detrusor overactivity and neurogenic detrusor overactivity. Because detrusor overactivity is a urodynamic diagnosis, it is possible to record symptoms and signs during urodynamic studies to correlate them with any involuntary contractions. The ICS 2002 report describes 2 types of detrusor overactivity: (1) phasic, which may or may not lead to urinary incontinence; and (2) terminal, which is a single involuntary detrusor contraction that often results in complete bladder emptying. OAB, as defined by ICS 2002, is a new term and is a symptomatic diagnosis. OAB is defined as urgency, with or without urge incontinence, and usually with frequency and nocturia.
A more general term used is lower urinary tract dysfunction. This all inclusive term applies to a cluster of distinguishable disorders however with common or largely overlapping symptomatology whose definitions continue to evolve as they become better understood. The symptoms are:                Urge or urgency (intense sensing that the bladder has reached its threshold)        Frequency of urination (8 ore more times per day)        Nocturia (sleep disturbance accompanying the need to urinate)        In some cases, obstruction of urine flow        In other cases, urinary incontinence        Urogenital or pelvic pain        
Disorders which are grouped under the term lower urinary tract dysfunction include:                Stress urinary incontinence (inability to prevent leakage of urine during activities that increase abdominal pressure)        Urge urinary incontinence: Incontinence episodes driven by detrusor overactivity        Mixed urinary incontinence (a mixture of both)        Overactive bladder syndrome: An inclusive term which not only included the above mentioned ones but also the “dry” overactive bladder without incontinence but with urgency, urinating frequency and nocturia. Overactive bladder is also seen frequently in children resulting in urgency, nocturia, and incontinence. Even in children, often pharmacological treatment is indicated to prevent incontinence, especially during the night (C. Persspm de Geeter 2004, Der Urologe Volume 7, page 807ff).        Benign prostatic hyperplasia/lower urinary tract symptoms: urinary storage difficulties typical of OAB plus obstruction of urinary flow, coincident with enlargement of prostatic mass        Neurogenic bladder: Catastrophic loss of bladder control on patients with spinal cord injury, stroke, multiple sclerosis, Parkinsons disease and other CNS diseases.        
All these diseases have one keys symptom in common: an imbalance of detrusor activity and sphincter activity of the bladder. In addition, all diseases are not primarily smooth muscle diseases, but rather are nervous system diseases as this delicate balance is established and maintained by central and peripheral nervous system activity.
While all the mentioned diseases relate to bladder function, a very similar situation can be found in a different disease, the irritable bowl syndrome (IBS). In IBS patients, a dys-regulation of gut function is central to the disease. While in most patients, this results in hypermotility and diarrhea, in others it results in hypomotility and constipation while in again other both, diarrhea and constipation can be observed. IBS is due to these colonic symptoms classified as either diarrhea predominant, constipation predominant or mixed type. While pain including abdominal pain is part of IBS symptomatology, it is to be noted that this invention is not directed to the pain as a secondary symptom of this disease but to the dys-regulation of gut function. However, in all these cases the disturbance can be expected to be found in the nerval control of the gut activity, i.e. in the intestinal nervous system and the control thereof. Current treatment of IBS often includes a combination of antidiarrheals, antispasmodics, and sometimes antidepressants.
The aim of the treatment in both cases, lower urinary tract dysfunction and IBS, is to restore the balance and to normal function focussing either on the nervous system control or directly on the smooth muscle function.
Lower urinary tract dysfunction is a very common disease with high prevalence, but often neglected. The prevalence of overactive bladder increases with age, ranging from 4.8% in females below age of 25 to 30.9% in those >65 years of age (P. Abrahams 2003, Urology Volume 62, Supplement 5B, page 28ff). Similar prevalence's can be found in male patients over the age of 65, however due to BPH. The prevalence of the other diseases are somewhat lower.
IBS, likewise, is also a very common disease and is also often neglected. The prevalence of IBS was found to be 12% among adults in the USA. The prevalence world wide can be expected to be similar (H. R. Mertz. Irritable bowel syndrome (Review article); New England Journal of Medicine 349:2136-46, 2003). New treatment is urgently needed since currently available, mostly symptomatic treatment is often insufficient and not free of side effects.
Current Treatment
Current treatment is mainly based on anticholinergic drugs, i.e. drugs which block the muscarine receptors. Such a pharmacological intervention is not entirely satisfactory. While the pharmacological effect, being statistically significant, may not be strong giving a 30% reduction in number of daily micturations only (getting the patients down from 15 times to approximately 11 times per day) even this small effect is associated with unpleasant side effects including mouth dryness, dry eyes and dry skin, constipation, and negative effects on cognition and memory. Other side effects include blurred vision and problems to accommodate. Further, central aspects of the disease, i.e. the urgency, is even less treated with such compounds. Currently, newer drugs with selectivity to the M3 subtype of the muscarine receptor, are about to be marketed. While the claim is, that they have a better separation between side effects and effects, this may not be fully correct. Constipation seems to be even a larger problem and efficacy is not improved. As the M3 receptor is also present in the eye, blurred vision and accommodation problems may remain.
Other drugs used include antidepressants, alpha1 adrenoceptor antagonists, and, for BPH only, 5alpha reductase inhibitors. Newer targets tested include 5HT receptor antagonists, potassium channel openers, and other targets. A list of targets currently evaluated in clinical trials can be found in an article from A. P. Ford, Drug Discovery World, Issue Fall 2003, page 9-17, which is herein incorporated by reference.
While current treatment for IBS often focuses on anti-diarrheals and antispasmodics, sometimes even antidepressants, anticholinergic drugs used for the treatment of incontinence are also active as they are good antidiarrheal agents. Newer drug targets include among others modulators of calcium activated potassium channels.
Based on this data review, we can conclude, that there is a well defined medical need for the development of new drugs for the treatment of OAB, and also more general for the treatment of lower urinary tract dysfunction. There also is an urgent need to for the development of newer drugs for the treatment of IBS. Such drugs should better address the over-activity which is a key symptom of both, IBS and OAB, without reducing the ability of the bladder detrusor to contract fully (in the case of OAB). This differentiation is essential. Drugs which are just relaxing smooth muscles often can also relax the detrusor muscle (and the sphincter muscle). Such relaxation, for example induced by calcium antagonists, may be active, but does result in two different risks. On one hand, the reduced contraction force can lead to residual volume remaining in the bladder. Such residual volume can be the cause not only for chronic infections but also for formation of cystic calculi. On the other hand, a plain smooth muscle relaxation also will relax the sphincter. In this case, the balance between sphincter activity and detrusor activity may not be positively influenced. Therefore, calcium antagonists are not in use for treatment of incontinence. Instead, calcium antagonists such as Diltiazem are used for the treatment of hypertension and angina pectoris due to their general effects to relax smooth muscles including vascular smooth muscles. Other drug targets are being evaluated, such as potassium channel openers with a focus on openers of the ATP sensitive potassium channel. However, while potent effects in models of hyperreactive bladder can be achieved, such drugs can not be used since they also relax smooth muscles of the vascular bed resulting in strong effects on blood pressure. Therefore none of these drug candidates has yet made it into a successful drug.
New drugs for the treatment of OAB should be active on the bladder detrusor activity without reducing the contraction force, should not or only slightly be active on vascular smooth muscles to avoid unwanted effects on blood pressure and should be safe with regard to other side effects including all cardiovascular side effects. New drugs for the treatment of IBS should normalize the activity of the overactive intestine without paralyzing the smooth muscle, i.e. they should not interfere with the ability of the gut to contract but rather interfere with the control of the gut motility.